1. Field of the Invention
This invention relates to a coating for an implantable device or an endoluminal prosthesis, such as a stent. The invention also relates to a biocompatible carrier containing an active agent for sustained release of the active agent to certain target cell population in a vascular region, such as smooth muscle cells, requiring modulation to ameliorate a diseased state, particularly for the treatment of stenosis or restenosis following a vascular trauma or disease. More specifically, the invention is directed to an ethylene vinyl alcohol composition and coating.
2. Description of the Background
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease. A catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially press against the atherosclerotic plaque of the lesion for remodeling of the vessel wall. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient""s vasculature.
A problem associated with the above procedure includes formation of intimal flaps or torn arterial linings which can collapse and occlude the conduit after the balloon is deflated. Moreover, thrombosis and restenosis of the artery may develop over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. To reduce the partial or total occlusion of the artery by the collapse of arterial lining and to reduce the chance of the development of thrombosis and restenosis, an expandable, intraluminal prosthesis, one example of which includes a stent, is implanted in the lumen to maintain the vascular patency.
Stents are used not only as a mechanical intervention but also as a vehicle for providing biological therapy. As a mechanical intervention, stents act as scaffoldings, functioning to physically hold open and, if desired, to expand the wall of the passageway. Typically stents are capable of being compressed, so that they can be inserted through small cavities via catheters, and then expanded to a larger diameter once they are at the desired location. Examples in patent literature disclosing stents which have been successfully applied in PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665 issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S. Pat. No. 4,886,062 issued to Wiktor. Mechanical intervention via stents, although a significant innovation in the treatment of occlusive regions, has not reduced the development of restenosis.
Biological therapy can be achieved by medicating the stents. Medicated stents provide for the local administration of a therapeutic substance at the diseased site. In order to provide an efficacious concentration to the treated site, systemic administration of such medication often produces adverse or toxic side effects for the patient. Local delivery is a preferred method of treatment in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Local delivery thus produces fewer side effects and achieves more favorable results.
One proposed method for medicating stents disclosed seeding the stents with endothelial cells (Dichek, D. A. et al. Seeding of Intravascular Stents With Genetically Engineered Endothelial Cells; Circulation 1989; 80: 1347-1353). Briefly, endothelial cells were seeded onto stainless steel stents and grown until the stents were covered. The cells were therefore able to be delivered to the vascular wall where they provided therapeutic proteins. Another proposed method of providing a therapeutic substance to the vascular wall included use of a heparin-coated metallic stent, whereby a heparin coating was ionically or covalently bonded to the stent. Significant disadvantages associated with the aforementioned methods include significant loss of the therapeutic substance from the body of the stent during delivery and expansion of the stent, lack of control of the release rate of the proteins from the stent, and the inherent limitation as to the type of therapeutic substance that can be used.
Another proposed method involved the use of a polymeric carrier coated onto the surface of a stent, as disclosed in U.S. Pat. No. 5,464,650 issued to Berg et al. Berg disclosed applying to a stent body a solution which included a specified solvent, a specified polymer dissolved in the solvent, and a therapeutic substance dispersed in the blend. The solvent was allowed to evaporate, leaving on the stent surface a coating of the polymer and the therapeutic substance impregnated in the polymer. Among the specified, suitable choices of polymers listed by Berg, empirical results were specifically provided for poly(caprolactone) and poly(L-lactic acid). The preferred choice of mutually compatible solvents included acetone or chloroform. As indicated by Berg, stents where immersed in the solution 12 to 15 times or sprayed 20 times. The evaporation of the solvent provided a white coating. A white coloration is generally indicative of a brittle polymeric coating. A brittle polymeric coating is an undesirable characteristic, since portions of the coating typically become detached during stent expansion. Detachment of the coating causes the quantity of the therapeutic substance to fall below a threshold level sufficient for the effective treatment of a patient.
Accordingly, it is desirable to provide an improved coating that is susceptible to expanding with a prosthesis without significant detachment from the surface of the prosthesis. It is also desirable for the coating to be able to strongly adhere to the surface of the prosthesis, thereby preventing significant loss of the polymeric coating during prosthesis delivery. It is also desirable to provide a benign or friendly solvent system that is capable of placing the polymeric material in dissolution without causing or propagating significant degradation of the therapeutic substance. Other desirable features include, but are not limited to, a polymeric coating which allows for a significant control of the release rate of a therapeutic substance, a polymeric solution which need not be applied excessively to the surface of the prosthesis to form a coating of a suitable thickness, and a polymeric solution that allows for the deposition of a more uniform coating.
In accordance with one aspect of the present invention, a coating for a prosthesis, such as a balloon-expandable stent, a self-expandable stent, or a graft, is provided. The coating includes an ethylene vinyl alcohol copolymer that has an ethylene content which makes the copolymer capable of dissolving in a solvent comprising iso-propyl alcohol and water. The copolymer can comprise a mole percent of ethylene of about 27% to about 29%. On commercial example of the copolymer is Soarnol(copyright).
In one embodiment, the copolymer can include an active agent such as actinomycin D, paclitaxel, or docetaxel. The active agent can be for inhibiting abnormal or inappropriate migration or proliferation of smooth muscle cells. In another embodiment, the copolymer can act as an intermediary tie layer between a metallic surface of the prosthesis and a coating layer carrying an active agent. In yet another embodiment, the copolymer can act as a diffusion barrier disposed over a coating layer carrying an active agent for reducing the rate at which the active agent is released from the coating layer.
In accordance with another aspect of the present invention, a therapeutic composition for inhibiting the narrowing of a region of a blood vessel is provided. The composition includes an ethylene vinyl alcohol copolymer and an active agent. The copolymer comprises a mole percent of ethylene monomer of about 27% to about 29%. The active agent can be released from the copolymer matrix to inhibit the narrowing of a region of the blood vessel. The narrowing can be caused by, for example, restenosis. Examples of agents include, actinomycin D, paclitaxel, or decetaxel.
In accordance with another aspect of the present invention, a method is provided for forming a coating for a prosthesis, such as a stent. The method comprises applying a composition including an ethylene vinyl alcohol copolymer and a solvent to the prosthesis to form a coating. The copolymer can include a mole percent of ethylene of about 27% to about 29%. The solvent includes iso-propyl alcohol and water such that the coating is formed by allowing the solvent to evaporate. In accordance with one embodiment, the composition that is applied to the prosthesis is heated to a temperature greater than about the glass transition temperature and less than about the melting temperature of the copolymer.
In accordance with one embodiment, the composition can additionally include an active agent for inhibiting restenosis or the narrowing of the blood vessel such that the active agent is releasably contained in the coating formed on the prosthesis. Examples of such agents include actinomycin D, paclitaxel, docetaxel, or analogs or derivatives thereof.